Charged aerosol detection is a popular and valuable technique for the detection and quantification of substances present in a liquid sample stream, and is particularly well-suited to use in connection with liquid chromatography applications. Briefly described, a charged aerosol detection (CAD) system consists of a nebulizer for generating a spray of droplets from a liquid sample stream (for example, the effluent from a chromatographic column), a discharge source for selectively charging the nonvolatile residue particles produced by drying the droplet spray, and a collector, where the aggregate charge imparted to the particles is measured using an electrometer. The resultant signal is in direct proportion to the quantity of analyte present and is representative of the concentration of the nonvolatile components of the sample stream. The CAD technique is sometimes referred to as a “universal” detection technique, as it is capable of quantifying a wide variety of nonvolatile substances with consistent response. Further details regarding the design, operation and advantages of CAD systems are set forth in U.S. Pat. No. 6,568,245 by Kaufman (“Evaporative Electrical Detector”), the disclosure of which is incorporated herein by reference.
A CAD system may be advantageously coupled as a detector to a High-Performance Liquid Chromatography (HPLC) system or other Liquid Chromatography (LC) system. The information provided by such a LC-CAD system is fundamentally different from that provided by LC systems employing other commonly used detectors (such as mass spectrometers) or UV-visible detectors) in that the CAD detection principle involves the measuring of charged solid aerosol particles that have a selected range of mobility rather than the measuring of individual gas-phase ions that are differentiated based upon m/z or analytes in solution that are differentiated based on optical absorption or fluorescence. Accordingly, CAD technology is able to quantify all analyte particles that acquire charge, including those that cannot ionize or do not have chromophores. It has been shown (R. C. Flagan, Aerosol Sci. Technol. 28, 1998)) that the signal obtained using CAD technology depends primarily upon particle size across a wide range and does not depend significantly upon individual analyte properties, such as chemical composition or chemical structure. The result is accurate and consistent response, regardless of analyte structure. Using charged aerosol detection, it is possible to measure any nonvolatile and most semivolatile analytes. A similar HPLC detection method, termed aerosol charge detection, has been described by R. W. Dixon and D. S. Peterson (Anal. Chem. 74, 2930-2937, 2002). The CAD technique can complement atmospheric pressure ionization MS techniques such as electrospray and APCI.
A schematic diagram of a conventional CAD device is shown in FIG. 1. The detection method includes pneumatic nebulization, at a nebulizer, of eluate received from an HPLC column 2 so as to create droplets 3. In known fashion, the HPLC column is fluidically coupled to and receives a sample liquid from an HPLC system 19 that may comprise several other components, such as one or more solvent supplies, injector valves, gradient valves for mixing solvents in controlled variable proportions, etc. The nebulizer may include a spray emitter 1 configured to break up a liquid into a spray of droplets and a spray chamber 17 configured to receive the spray of droplets and cause evaporation of volatile substances such that only dried particles 6, comprising non-volatile analytes, remain. A gas inlet 7 provides a flow of gas that is divided at a gas-splitting junction 8 into a flow 9a of nebulizing gas that is provided to the spray emitter 1 through a first gas conduit 34a and a flow 9b of reagent gas that is provided to a charging chamber 11 through a second gas conduit 34b that causes the reagent gas to flow past an ionization source 10, such as a corona needle before entering the charging chamber 11. If the ionization source 10 comprises a corona needle, the corona needle is maintained, during operation, at a high applied voltage by voltage supply 35.
The spray emitter 1 of the conventional CAD device shown in FIG. 1 is configured such that the flow of nebulizing gas is introduced at an approximately right angle relative to the direction of flow of liquid into the nebulizer and such that the generated droplets are caused to collide at high velocity with the surface of an impactor 4. The largest of the initial droplets 3 are broken up into smaller droplets upon collision with the impactor 4 and the resulting small droplets remain entrained in a portion of the nebulizing gas flow along a path through a conduit 18. Any remaining large droplets or droplets that are too large to be entrained in the gas flow into conduit 18 are directed to waste via a drain port 5. The droplets passing through conduit 18 undergo ambient-temperature solvent evaporation so as to yield an aerosol of analyte solid particles 6 suspended in the gas flow 9a. A turbulent jet of positive ions 12, formed by passing the reagent gas stream 9b past the ionization source and through an orifice, is mixed, in a charging chamber 11, with the opposing-flow stream of analyte aerosol particles 6. In this process, charge is transferred diffusionally to analyte particles. Excess positive ions and smaller, high mobility, negatively and positively charged particles are trapped or neutralized by a weak electric field applied by electrode 16 and the charged analyte particles 13 impinge on a conductive filter 14, which transfers the charge to an electrometer 15 for signal transduction.
The response curve for CAD and other aerosol detectors is often described by the following equation:S=a[Amount]b  Eq. 1in which S represents observed signal (e.g., fA m3 particles−1) and where the pre-exponential coefficient (a) indicates absolute sensitivity and the exponent (b), referred to herein as the power law, describes the shape of the response curve. At any point on a response curve, sensitivity can be described by the slope of the curve:a=S/[Amount]  Eq. 2
In practice, b≠1, sensitivity changes as a function of analyte amount and the instrument response is therefore non-linear.
Dixon and Peterson (“Development and testing of a detection method for liquid chromatography based on aerosol charging.” Analytical chemistry 74(13), 2002, pp. 2930-2937) describe that:Dp=Dd(C/ρ)1/3  Eq. 3in which Dp=dried particle diameter, Dd=initial droplet diameter C=droplet residue concentration, and ρ is the density of the particle. Thus, the average particle size increases with the amount of particle-forming analytes in the original sample. Dixon and Peterson further describe that:S=1.61×10−10Dp1.11 (for Dp>10 nm)  Eq. 4aS=2.30×10−16Dp6.6 (for Dp≤10 nm)  Eq. 4b
The above equations show that the signal response of CAD is intrinsically non-linear. The non-linearity is most evident in experimental results spanning a wide dynamic range. Cohen and Liu (“1 Advances in Aerosol.” Advances in chromatography 52, 2014)) state that “All aerosol-based detectors exhibit a nonlinear response over large concentration ranges, and this is a major limitation for these detectors seeing greater use.” Likewise, Hutchinson et al (“Universal response model for a corona charged aerosol detector.” Journal of Chromatography A 1217(47), 2010, pp. 7418-7427) state that “A significant barrier to the implementation of the aerosol detectors has been that they exhibit non-linear calibration curves.” Combination of Eq. 3 with Eq. 4a predicts that, for sufficiently large analyte particles, the signal, S, should obey an overall approximately ⅓ power law with concentration as the multiplicative product of individual power laws of ⅓ and 1.11. A power law response has been observed in various experimental results (i.e., FIGS. 9-12) set forth in U.S. Pat. No. 6,568,245 in the name of inventor Kaufman. Accordingly, experimental results illustrated in that patent represent the detector signal (current) raised to the 3rd power so as to approximate a linear response. However, the same patent also states that “In actual practice . . . detector electrical current has been found to vary more closely in proportion to the square-root of the concentration rather than the cube-root. This may be caused by coagulation in the aerosol, effects of analyte concentration on nebulizer performance, or other factors presently unknown.”
Such non-linear response is commonly viewed as the single most significant limitation of LC-aerosol detectors. Further, solvent dependency of response during solvent gradient LC separations is often considered to be an almost equally significant limitation. Solvent dependency mainly refers to changes in response attributed to changes in primary aerosol characteristics, transport and evaporation. The main solvent properties of interest are surface tension, viscosity and density. An important consideration is solvent load especially for water since, except for very low liquid flow rates, the aerosol is expected to be supersaturated with water vapor.